Substituted phenoxyalkyl quaternary ammonium compounds as antiarrhythemic agents

ABSTRACT

Quaternary ammonium compounds such as [2-(4-amino-2,6-dibromophenoxy)ethyl[dimethyl (allyl) ammonium bromide are prepared by the reaction of a tertiary amine such as 3,5-dibromo-β-dimethylamino-p-phenetidine with a substituted organic compound such as allyl bromide. The quaternary ammonium compounds are useful in alleviating or inhibiting cardiac arrhythmias when the quaternary ammonium compounds, or compositions comprising the same are administered to animals.

CROSS-REFERENCE TO RELATED APPLICATION

This is a division of application Ser. No. 164,086, filed July 19, 1971,now U.S. Pat. No. 3,875,215.

BACKGROUND OF THE INVENTION

The compounds of the present invention are substituted phenoxyalkylquaternary ammonium compounds. Various ether phenoxyalkyl quaternaryammonium compounds have been described by Hey, Brit. J. Pharmacol. 7,117 (1952); Hey and Willey, Brit. J. Pharmacol. 9, 471 (1954) and U.S.Pat. No. 2,895,995; and by Jones et al., Biochem. J. 45, 143 (1949).

SUMMARY OF THE INVENTION

This invention is directed to quaternary ammonium salt compounds, and toa method and composition utilizing such compounds. More particularly,the invention is concerned with quaternary ammonium salt compoundscorresponding to the formula: ##SPC1##

Wherein Y represents amino, loweralkylamino or diloweralkylamino; R₁ andR₂ represent lower alkyl; R₁ and R₂ independently taken togetherrepresent an aliphatic hydrocarbon moiety of from 4, to 5, to 6 carbonatoms, which can be substituted with zero, one, or two lower alkylsubstituents, R₁, R₂ and the quaternary nitrogen forming a 5, 6 or7-membered ring; R₃ represents lower alkenyl, phenacyl, mono-, di ortrihalophenacyl, lower alkynyl, substituted lower alkyl, substitutedlower alkenyl or substituted lower alkynyl in which such moieties aresubstituted with one substituent selected from halogen, phenyl,halophenyl, dihalophenyl, trihalophenyl, nitrilo, hydroxy, carboxyalkyland keto; or R₁, R₂ and R₃ taken together represent a quinuclidineresidue; X₁ and X₂ both represent halogen; A⁻ represents astoichiometric equivalent quantity of a pharmaceutically-acceptableanion; n represents one of the integers 2, 3 or 4; HX represents astoichiometric equivalent quantity of a pharmaceutically-acceptableacid; and m represents one of the integers 0 and 1. The quaternaryammonium salt compounds are crystalline solids which are soluble inwater, and of varying degrees of solubility in organic liquids such asdimethyl formamide, esters, halohydrocarbons, alcohols and the like.

In the present specification and claims, the term "halogen" is employedwith respect to the moieties X₁, X₂ and R₃ of the above formula todesignate one of the halogens chlorine, bromine and iodine, and the term"lower alkyl" is employed to designate lower alkyl of from 1, to 2, to3, to 4, to 5, to 6 carbon atoms, the term "carboxyalkyl" is employed todesignate such moieties containing from 2, to 3, to 4, to 5 carbonatoms. The terms "lower alkenyl" and "lower alkynyl" are employed todesignate such moieties containing from 2, to 3, to 4, to 5, to 6 carbonatoms. The terms "pharmaceutically-acceptable anion" and"pharmaceutically-acceptable acid" as herein employed, refer tonon-toxic anions or acids employed in quaternary ammonium salt compoundsor acid-addition salts thereof. The terms include the acidic or anionicmoieties which have no substantial toxicity or detrimentalpharmacological effect when a quaternary ammonium salt compoundincluding such an anion is administered to animals at dosages consistentwith good pharmacological activity and acids of such moieties. Suchpharmaceutically-acceptable anions include non-toxic inorganic anionssuch as the chloride, bromide, iodide, sulfate, nitrate, bisulfate orphosphate, or organic anions such as the acetate, propionate, succinate,malate, fumarate, glutamate, salicylate, maleate, tartrate or citrateanions, organic sulfonate anions such as the camphorsulfonate,methanesulfonate, benzenesulfonate or toluenesulfonate anions. Themethanesulfonate, benzenesulfonate, chloride and bromide anions areparticularly useful in the preparation, purification and use of thequaternary ammonium salts of the invention and are preferredpharmaceutically-acceptable anions.

The compounds of the invention are useful in the study of drug effectsupon cardiac activity in animals, and have been found to be particularlyuseful as antiarrhythmic agents. The compounds can be employed incombatting cardiac arrhythmias in animals by administering anantiarrhythmic amount of one or more of the quaternary ammonium saltcompounds to an animal. In such use, the compounds are administeredinternally to the animal to introduce the compound into the animal'scardiovascular system. The compounds can be administered parenterally byintraperitoneal, subcutaneous or intravenous injection, for example, andtypically by intravenous injection. In contrast to many known quaternaryammonium compounds, the quaternary ammonium salt compounds of theinvention can also be administered to animals via the gastrointestinaltract, typically by oral administration. The compounds have excellentantiarrhythmic activity both therapeutically, in administration to ananimal suffering from a cardiac arrhythmia, and prophylactically toprotect an animal against the occurrence or recurrence of arrhythmias,typically in an animal subject to arrhythmias.

The terms "arrhythmic", "cardiac arrhythmia" and "arrhythmia" asemployed herein refer to irregular cardiac activity characterized byirregular beating of the heart, that is, non-rhythmic heart beat. Sucharrhythmias involve substantial departures from the regular,substantially sinus (sinusoidal) normal heart beat. Arrhythmias aregenerally beyond the normal increased, but still substantially regular,heart beat rate resulting from physical activity. The term is inclusiveof the conditions described by terms such as ventricular fibrillation,ventricular tachycardia, atrioventricular nodal beats, auricularflutter, auricular fibrillation or premature ventricular contractions.The terms "arrhythmic animal" and "arrhythmic mammal", as employed inthe present specification and claims, mean and refer to animalssuffering cardiac arrhythmias. Such arrhythmias can be the result ofphysiological or pathological conditions. They can also be brought aboutby physical conditions such as electrical stimulation or physical injuryor they can result from pharmacological effects such as theadministration of compounds such as digitalis or similar compounds suchas ouabain, acetyl strophanthidin, deslanoside C or digitoxin;epinephrine; ergot; chloroform; cyclopropane and the like having cardiacstimulant and arrhythmia-inducing activity or side effects.

In the practice of the method of the invention, a quaternary ammoniumsalt compound is normally incorporated in a pharmaceutical carrier andthe resulting composition is administered internally to an animal. Inthe present specification and claims, "pharmaceutical carrier" refers toknown pharmaceutical excipients which are substantially non-toxic andnon-sensitizing at dosage levels consistent with good antiarrhythmicactivity. The active ingredient is preferably administered parenterallyin the form of liquid injectable solutions or suspensions, and orally inthe form of solid compositions which can be prepared by known techniquessuch as tableting and encapsulation. Suitable pharmaceutical carrierswhich can be employed for formulating the solid compositions includestarch, lactose, glucose, sucrose, gelatin, powdered licorice, malt,rice flour, chalk, silica gel, hydroxyethyl cellulose, hydroxypropylcellulose, magnesium carbonate, magnesium stearate, carboxymethylcellulose, and the like and compatible mixtures thereof. The quaternaryammonium compounds can also be formulated as liquid compositionsincluding syrups, elixirs, suspensions and emulsions for oraladministration. Among the liquid pharmaceutical carriers which can beemployed for orally-administered compositions are ethanol, water,saline, glucose syrup, syrup of acacia, mucilage of tragacanth,propylene glycol, polyethylene glycols, peanut oil, wheat germ oil,sunflower seed oil or corn oil and the like and compatible mixturesthereof. Orally-ingestible compositions can include emulsifying agentssuch as lecithin, sorbitan trioleate, polyoxyethylene sorbitanmonooleate and natural gums such as gum acacia and gum tragacanth, andsuspending agents such as polyethylene oxide condensation products ofalkylphenols or fatty acids or fatty alcohols, or cellulose derivativessuch as carboxymethyl cellulose or hydroxypropylmethyl cellulose. Thecompositions can also contain sweetening agents such as sucrose, orsaccharin, flavoring agents such as caramel, coloring materials,preservatives and the like.

Injectable compositions adapted for parenteral administration such asintramuscular, subcutaneous or, preferably, intravenous injection can beprepared with pharmaceutical carriers which are liquidparenterally-acceptable vehicles, i.e., liquid pharmaceutical carrierswhich are adapted for use in formulating parenteral preparations andwhich are substantially non-toxic and non-irritating when administeredparenterally at dosages consistent with good antiarrhythmic activity.Representative liquid parenterally-acceptable vehicles includepyrogen-free water, normal saline solutions, Ringer's Injection,Lactated Ringer's Injection, dextrose solutions, ethanol, propyleneglycol, liquid polyethylene glycols, fixed vegetable oils such as cornoil, peanut oil or cottonseed oil, ethyl oleate, isopropyl myristate andthe like. The injectable compositions can also contain other materialssuch as preservatives, buffers and the like. Preferred injectablecompositions comprise a sterile solution of the quaternary ammonium saltcompound in the parenterally-acceptable vehicle. The compositions can beformulated by using conventional procedures such as are described inRemington's Pharmaceutical Sciences, 13th Ed., Chapter 36, Mack Publ.Co., Easton, Pa. (1965).

The selection of the exact pharmaceutical carrier to be employed in anygiven circumstance can be carried out by routine and conventional rangefinding operations to arrive at formulations having the desiredcharacteristics of physical form, ease of administration in a desiredroute, storage stability, etc.

The antiarrhythmic amount of the quaternary ammonium salt compounds tobe administered to an animal can vary depending upon such factors aswhether or not the animal is suffering from an arrhythmia at the time ofadministration, the type and severity of arrhythmia exhibited, themethod and frequency of administration, the exact anti-arrhythmic effectto be produced, the particular quaternary ammonium salt compoundsemployed and the species, size, weight, age and physical condition ofthe particular animal being treated. In general, when the animal isactively exhibiting arrhythmia, it is preferred to administer thecompound at an antiarrhythmic dosage rate sufficient to bring about acomplete conversion of the arrhythmia to normal sinus cardiac activity.In such operations, the active compound is preferably introduceddirectly into the cardiovascular system of the animal to provide anantiarrhythmic concentration of the quaternary ammonium salt compound inthe cardiovascular system, particularly at the heart. In a convenientprocedure, the compound is administered by intravenous injection at aninitial antiarrhythmic dosage less than that required to fully convertthe arrhythmia to normal rhythm, and the heartbeat of the animal ismonitored as the amount of compound administered is gradually increasedover a period of minutes until an antiarrhythmic amount sufficient tofully convert the arrhythmia to rhythmic cardiac activity has beenadministered. It is then preferred to supply the compound in periodicmaintenance antiarrhythmic dosages, such administration being either bythe same parenteral route, or by administration of larger antiarrhythmicdosages by another route such as orally. The maintenance antiarrhythmicdosage and mode of administration are selected to provide a more-or-lesscontinuous antiarrhythmic concentration of the quaternary ammonium saltcompound in the cardiovascular system, such concentration beingsufficient to inhibit further arrhythmia. In general, the quaternaryammonium compound can be administered intravenously in initial dosagesof from about 0.1 or less to about 15 or more milligrams per kilogram ofanimal body weight, providing initial antiarrhythmic concentrations inthe cardiovascular system. Maintenance dosages can vary widely dependingupon a variety of factors such as the time and frequency ofadministration, the exact compound or compounds employed, the condition,size, age and species of the animal, the route of administrationselected, the type of dosage form employed, the type and cause of thearrhythmia, and the length of time during which a maintenance dose isdesired. In cases in which there is little or no likelihood ofrecurrence of arrhythmia once conversion has been brought about, themaintenance dosage can comprise a continuation of the initialintravenous antiarrhythmic dosage for a relatively brief period. Whenrecurrence of arrhythmia is likely, the maintenance dosage can compriserepeated oral administration of an antiarrhythmic amount of thecompounds over extended periods. Maintenance dosages can be administeredby single or multiple doses provided that the compounds are administeredin an antiarrhythmic amount sufficient substantially to alleviatecardiac arrhythmia.

A preferred group of the quaternary ammonium salt compounds comprisesthe compounds corresponding to the above formula I wherein R₁ and R₂ areboth methyl or both ethyl, wherein Y is amino and wherein X₁ and X₂ areboth bromine or both chlorine. It is also generally preferable that themoieties R₁ and R₂ together contain from 2 to 6 carbon atoms; that themoiety R₃ contain from 3 to 7 carbon atoms and that R₁, R₂ and R₃together contain from 5 to 9 carbon atoms. Other preferred groups ofcompounds include those wherein Y is amino, R₃ is lower alkenyl or loweralkynyl of 3 to 4 carbon atoms or those wherein R₃ is substituted loweralkyl, lower alkenyl or lower alkynyl of from 2 to 4 carbon atomssubstituted with a single bromo, chloro, keto or nitrilo substituent,and those wherein R₃ is benzyl, monohalobenzyl and dihalobenzyl. Afurther preferred group comprises the compounds corresponding to theabove formula wherein n is 2, Y is amino, X₁ and X₂ are bromine, R₁ andR₂ are methyl, and R₃ is lower alkenyl or lower alkynyl of 3 or 4 carbonatoms, and A⁻ is chloride or bromide anion. This latter group ofquaternary ammonium salts thus corresponds to the formula ##SPC2##

wherein m, HX and A⁻ have the significance set out above with respect toformula I and R₃ is lower alkenyl or lower alkynyl of 3 or 4 carbonatoms, preferably 2-propynyl, allyl or 2-methylallyl. The preferredcompounds of Formula Ia provide excellent antiarrhythmic results of longduration when administered orally or parenterally in relatively lowdosages and are particularly preferred for combatting cardiacarrhythmias.

PREPARATION OF THE COMPOUNDS

The quaternary ammonium salt compounds of the invention can be preparedby the reaction of a tertiary amine compound corresponding to formula II##EQU1## with a substituted organic alkylating agent corresponding toformula III

    R'''' -- B                                                 III

In the above formulae II and III, one of the substituent moieties R',R",R'", and R"" represents a substituted phenoxyalkyl moiety correspondingto formula IV ##SPC3##

wherein X₁, X₂, Y and n all have the significance set out above withrespect to formula I; and each of the remaining substituent moieties R',R", R'" and R"" represents a different individual one of the moietiesR₁, R₂ and R₃ as set out above with respect to formula I and Brepresents a pharmaceutically-acceptable strongly anionic moiety such ashalide, alkyl or aryl sulfonate, sulfate or phosphate. Thus thesubstituted phenoxyalkyl moiety of formula IV can be provided as asubstituted phenoxyalkylamine or as a substituted phenoxyalkyl halide,and the R₁, R₂ and R₃ moieties similarly can be provided by a tertiaryamine compound of formula II or by a substituted organic compound offormula IV. Representative tertiary amines which can be employed asstarting materials include N-methyl-N-ethyl-N(2-propynyl) amine;dimethyl phenethylamine; N,N-diethyl-N-4-chlorobutylamine; N-2-butenyldimethylamine; N-allyl-pyrrolidine; picoline, lutidine; quinuclidine;3,5-dibromo-β-dimethylamino-p-phenetidine;3,5-diiodo-β-(N-3-nitrilopropyl-N-ethyl)amino-p-phenetidine;3-chloro-5-bromo-4-[2-(N-2,4,5-trichlorobenzyl-N-methylamino)propoxy]-N-butyl aniline; N,N-diethyl-N-(2-methylallyl) amine;N-butyl-N-[3-(2,5-diiodophenyl)propyl]-N-[3-(2,6-dichloro-4-aminophenoxy)propyl]amine;3,5-dichloro-4-[3-(N-3-nitrilopropyl-N-methylamino)propoxy]-N,N-dimethylaniline;3,5-dibromo-4-[β-N-(3-butynyl)-N-methyl amino ethoxy]-N-ethylaniline;N-[β(2-bromo-4-amino-6-iodophenoxy)-ethyl]-N-(2-methylallyl)-N-ethylamine;N-allylpiperidine;3,5-dichloro-β-(N-isopropyl-N-methyl)amino-p-phenetidine; and3,5-dibromo-β-(N-3-ketobutyl-N-methyl)amino-p-phenetidine.Representative substituted organic compounds can include propargylbromide, propargyl chloride, 3,5-dibromo-4-(2-bromoethoxy)aniline;3,5-dichloro-4-(3-bromopropoxy) N,N-dimethylaniline, β-cyanoethyltosylate; 1-(2-bromo-6-chlorophenoxy)-(2-bromoethane); propenylchloride, chlorohexane, methyl bromide, ethylene dibromide, benzylbromide, 3,4,5-trichlorophenethyl bromide, chloroacetone,1,4-dichloro-2-butene, butyl bromide, 1-chloro-2-methyl propane,1-chloro-3-cyanopropane, 1,1,3-trichloropropane, 1-bromo-4-phenylbutane,and 3,4,5-trichlorophenacyl bromide.

The reaction proceeds when the reactants are contacted and mixed,preferably in the presence of an inert organic liquid such asacetonitrile or dimethyl formamide as a reaction medium. In preparingthe quaternary ammonium compounds of the invention, the substitutedhalophenoxyalkyl amine compound of formula II and the organic compoundof formula III are selected from such compounds in which the R', R", R'"and R"" moieties are such as to provide the R₁, R₂ and R₃ moietiesdesired in the quaternary product. The reaction proceeds readily attemperatures of from about 10° to about 100°C., and is preferablycarried out at a temperature from about 25° to about 70°C. The exactproportions of the reactants to be employed are not critical, howeverthe formation of one molar proportion of the quaternary ammonium saltproduct requires one molar proportion of each of the tertiary amine andsubstituted organic reactants, and the reactants are preferably employedin such proportions. The reaction of the tertiary amine and organiccompound proceeds with the evolution of heat and the production of aquaternary ammonium salt product wherein the anionic moiety is theanionic moiety B of the organic compound of formula III. In those casesin which the product separates as a precipitate in the reaction mixture,the product can be separated by conventional procedures such asfiltration, decantation, centrifugation. In cases in which the productdoes not precipitate from the reaction mixture, the quaternary ammoniumsalt can be separated by other conventional procedures such asevaporation under reduced pressure, cooling of the reaction mixture andscratching or seeding to induce crystallization, dilution with organicliquids such as ethyl acetate, benzene or butyl acetate or the like. Theproduct can be purified by conventional procedures such asrecrystallization and washing.

The anionic moiety A⁻ of the quaternary ammonium salts corresponding toformula I can be varied by conversion of one salt to another byconventional procedures for anion exchange. The exchange can be carriedout, for example, by the methathetic reaction of one of the quaternaryammonium salts of the invention with the desired anion in the presenceof a cation which forms a methathesis reaction product with the anionicmoiety to be replaced, and methathesis reaction product being insolublein the reaction medium employed for the metathetic reaction. In aconvenient procedure a quaternary ammonium halide of the invention isprepared as described above using a reactant corresponding to formulaIII wherein A is halogen, such as chlorine or bromine. The quaternaryammonium halide is dissolved in aqueous ethanol at room temperature andthe solution is mixed with an aqueous solution of an acid supplying thedesired anion, e.g., sulfuric acid. The haldie is removed as hydrogenhalide by fractional distillation and the methathesis quaternaryammonium salt product is separated and purified by conventionalprocedures. Alternatively, different anionic moieties can be introducedinto the quaternary ammonium salt compounds of formula I by passing anaqueous solution of a compound of formula I through an anion-exchangeresin saturated with the anion desired in the product.

In the preparation of the quaternary ammonium salts of the inventionwherein R₁, R₂ and R₃ represent a quinuclidine, pyridine, picoline orlutidine residue, the substituted phenoxyalkyl moiety is convenientlysupplied as a substituted phenoxyalkyl halide. The tertiary aminereactant is a substituted nitrogen-containing heterocyclic amine such asquinuclidine, pyridine, α-picoline, 3,4-dimethyl pyridine or the like.The quaternization reaction is conveniently carried out undersubstantially the conditions described above.

The pharmaceutically-acceptable acid addition salt form of thequaternary ammonium compounds, that is, those quaternary ammonium saltsof formula I wherein m is 1, are prepared according to conventionalprocedures for forming acid addition salts of primary, secondary ortertiary amines. In a convenient procedure, a quaternary ammonium saltcorresponding to formula I wherein m is 0 is taken up in a minimalamount of a lower alkanol and the mixture is treated with an excess ofthe desired pharmaceutically-acceptable acid in ether or dioxane. Thesalt is separated and purified by conventional procedures.

In a convenient procedure for the preparation of the quaternary ammoniumsalts of the invention wherein R₁ and R₂ represent lower alkyl, thetertiary amine reactant employed is a substituted 3,5-dihalophenoxyalkylamine corresponding to the above formula II wherein R' and R"represent the R₁ and R₂ lower alkyl moieties as described above withrespect to formula I and R'" represents a substituted phenoxyalkylmoiety corresponding to the above formula IV. Such tertiary aminestarting materials can be prepared readily by the reaction of asubstituted phenoxyalkyl halide with a dialkyl amine by the proceduresdescribed in U.S. Pat. No. 3,389,171 or by analogous procedures. Thesubstituted organic compound reactant employed is a compound of formulaIII above wherein R"" represents R₃ as described with respect to formulaI and B represnts halo, alkyl sulfonyl or aryl sulfonyl. In suchprocedure, the substituted halophenoxyalkylamine is dispersed in aninert organic liquid such as dimethylformamide or acetonitrile, and anequimolar proportion of the organic compound of formula III is addedgradually and mixed therewith. The reaction mixture is maintained at atemperature within the reaction temperature range for a period of 1 to36 hours. In those cases in which the product does not separate from thereaction mixture, the product can be conveniently separated by dilutingthe reaction mixture with several volumes of ethyl acetate. In thosecases in which a crystalline product is not obtained upon dilution withethyl acetate, the product can be crystallized by treating the ethylacetate mixture with excess pharmaceutically-acceptable acid,trituration, or crystallization from other organic liquids such asmethanol, ethanol, or isopropanol. The product can be purified byconventional procedures such as recrystallization and washing.

DESCRIPTION OF PREFERRED EMBODIMENTS

The following examples are illustrative of the invention.

EXAMPLE 1

3,5-Dibromo-β-dimethylamino-p-phenetidine (25.4 grams; 0.075 mole) isdissolved in 200 milliliters of acetonitrile at room temperature.2-Methylallyl chloride (6.9 grams; 0.075 mole) is rapidly added dropwiseto the solution with stirring, during which time a temperature rise of3°-4° C. is observed. The reaction mixture is heated at a temperature of55°-65°C. for 4 hours with continued stirring. Formation of aprecipitate is observed in the mixture, beginning about 15 minutes afteraddition of the 2-methallyl chloride and continuing through the heatingperiod. The reaction mixture is then cooled in an ice bath and filtered.The [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl-(2-methylally)ammoniumchloride product is collected as a filter cake, dried in air and foundto melt at 185°-186°C. The product is dissolved in hot isopropanol andthe solution treated with activated carbon and filtered. The solution iscooled, whereupon a crystalline solid precipitate forms, and filtered.The purified[2-(4-amino-2,6-dibromophenoxy)ethyl]-dimethyl(2-methylallyl)ammoniumchloride product is collected as a filter cake, dried under reducedpressure, and found to melt at 181°-182°C. The structure of the product,corresponding to the formula: ##SPC4##

is confirmed by infrared and nuclear magnetic resonance spectroscopy.The product is found by combustion analysis to have carbon, hydrogen andnitrogen contents of 39.35, 4.98 and 6.64 percent, respectively, ascompared with the theoretical contents of 39.2, 4.94 and 6.54 percent,respectively, calculated for the named structure.

EXAMPLE 2

3,5-Dibromo-β-dimethylamino-p-phenetidine (16.9 grams; 0.05 mole) isdissolved in 50 milliliters of dimethyl formamide at a temperature ofabout 25°C. To this solution is added dropwise with stirring ethylbromoacetate (9.2 grams; 0.055 mole). During the addition the mixturewarms spontaneously to a temperature of about 49°C., and the mixture iscooled to 27°C. prior to addition of the final 2 grams of ethylbromoacetate. A precipitate forms in the reaction mixture after theaddition is complete, and 50 milliliters of additional dimethylformamide is added. The mixture is stirred for one hour, then held overnight at room temperature. The crystalline solid product is collected asa filter cake by suction filtration of the mixture and the filter cakeis recrystallized from boiling ethanol. The[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(ethyl carboxymethyl)ammonium bromide is obtained as a light tan crystalline solid, meltingat 187°-188°C. The product is found by combustion analysis to havecarbon, hydrogen and nitrogen contents of 33.5, 4.3 and 5.6 percent,respectively, as compared with the theoretical contents of 33.3, 4.2 and5.6 percent, respectively, calculated for the named structure. Thestructure of the product is confirmed by infrared spectroscopy andnuclear magnetic resonance analysis.

A second crop of the product is obtained by diluting the dimethylformamide reaction mixture filtrate with excess ethyl acetate, andcollecting the resulting precipitate by filtration. This crop of theproduct is dried, crystallized from acetonitrile and found to havenuclear magnetic resonance and infrared spectra consistent with theassigned structure, and in excellent agreement with the spectra obtainedwith the first crop.

EXAMPLE 3

3,5-Dibromo-β-dimethylamino-p-phenetidine (20.3 grams; 0.06 mole) and2-chlorobenzyl chloride (9.7 grams; 0.06 mole) are dissolved in 200milliliters of acetonitrile. The reaction mixture is heated at atemperature of about 35° C. for about 1 hour and then at ambienttemperature overnight with continued stirring. Formation of aprecipitate is observed in the mixture, beginning about one hour afterinitial contacting of the reactants. The reaction mixture is filtered,and the[2-(4-amino-2,6-dibromophenoxy)-ethyl]dimethyl(2-chlorobenzyl)ammoniumchloride product is collected as a filter cake, dried in air, andrecrystallized from isopropanol. The purified[2-(4-amino-2,6-dibromophenoxy)-ethyl]dimethyl(2-chlorobenzyl)ammoniumchloride product is found to melt at 172°-173°C. The structure of theproduct is confirmed by infrared and nuclear magnetic resonancespectroscopy. The product is found by combustion analysis to havecarbon, hydrogen and nitrogen contents of 41.3, 4.3 and 5.8 percent,respectively, as compared with the theoretical contents of 40.9, 4.0 and5.6 percent, respectively, calculated for the named structure.

EXAMPLE 4

3,5-Dibromo-β-dimethylamino-p-phenetidine (16.9 grams; 0.05 mole) isdissolved in 35 milliliters of dimethyl formamide and the solution iscooled in an ice-bath to a temperature of about 10°C. To this solutionis added dropwise with stirring propargyl bromide (6.5 grams; 0.055mole). During the addition the mixture warms spontaneously to atemperature of about 18°C., and the mixture is cooled to 10°C. prior toaddition of the final amounts of propargyl bromide. The mixture isallowed to warm to room temperature then heated at a temperature of45°C. for 1 hour and diluted with ethyl acetate, whereupon thecrystalline solid product separates. The product is separated byfiltration of the mixture, recrystallized once from a mixture ofisopropanol and ethanol and recrystallized a second time from a mixtureof ethanol and ethyl acetate. The[2-(4-amino-2,6-dibromo-phenoxy)ethyl]dimethyl(2-propynyl)ammoniumbromide product is obtained as a yellow crystalline solid melting at166°-168°C. The product is found by combustion analysis to have carbon,hydrogen and bromide contents of 34.5, 3.8 and 52 percent, respectively,as compared with the theoretical contents of 34.2, 3.8 and 52.5 percent,respectively, calculated for the named structure. The structure of theproduct is confirmed by infrared spectroscopy and nuclear magneticresonance analysis.

EXAMPLE 5

3,5-Dibromo-β-dimethylamino-p-phenetidine (25.4 grams; 0.075 mole) isdissolved in 200 milliliters of acetonitrile at room temperature.Chloroacetone (7.0 grams; 0.075 mole) is rapidly added dropwise to thesolution with stirring, during which time a slight temperature rise isobserved. The reaction mixture is heated at a temperature of 55°-65°C.for 4 hours with continued stirring, then cooled in an ice bath andfiltered. The[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(acetonyl)ammonium chlorideproduct is collected as a filter cake, dried in air, and recrystallizedfrom isopropanol. The purified[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(acetonyl)ammonium chlorideproduct is obtained as a tan crystalline solid melting at 181°-182°C.The structure of the product is confirmed by infrared and nuclearmagnetic resonance spectroscopy. The product is found by combustionanalysis to have carbon, hydrogen and nitrogen contents of 36.1, 4.6 and6.4 percent, respectively, as compared with the theoretical contents of36.3, 4.5 and 6.5 percent, respectively, calculated for the namedstructure.

EXAMPLE 6

3,5-Dibromo-β-dimethylamino-p-phenetidine (16.9 grams; 0.05 mole) isdissolved in 35 milliliters of dimethyl formamide at a temperature ofabout 25°C. Allyl bromide (6.7 grams; 0.055 mole) is added dropwise tothe solution with stirring. During the addition the mixture warmsspontaneously to a temperature of about 32°C. The mixture is then heldovernight at room temperature. The mixture is diluted with a largeexcess of ethyl acetate, whereupon a yellow amorphous solid separates.The solid product is separated by decantation, washed with ethyl acetateand crystallized by trituration with isopropanol. The product isrecrystallized once from hot isopropanol and a second time from anethanol-ethyl acetate mixture. The[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(allyl)ammonium bromideproduct is obtained as a yellow crystalline solid melting at157.5°-159°C. The product is found by combustion analysis to havecarbon, hydrogen and bromide contents of 33.8, 4.2 and 52.0 percent,respectively, as compared with the theoretical contents of 34.0, 4.2 and52.2 percent, respectively, calculated for the named structure. Thestructure of the product is confirmed by infrared spectroscopy andnuclear magnetic resonance analysis.

EXAMPLES 7-14

In procedures similar to those employed in Examples 1-6 above,2,6-dibromo-β-dimethylamino-p-phenetidine is quaternized withappropriate organic alkylating reactants to produce quaternary ammoniumsalt compounds of the invention. The compounds correspond to formula Iabove wherein m is zero, Y is amino, n is 2, X₁ and X₂ are both bromoand R₁ and R₂ are methyl. The compounds obtained, identified by the R₃and A⁻ moieties, and the organic reactants reacted with the saidphenetidine compounds are set out in the following table.

    __________________________________________________________________________    Ex.      R.sub.3 A.sup.-                                                                            Melting Alkylating                                                            Point °C.                                                                      Reactant                                        __________________________________________________________________________    7    2-hydroxyethyl                                                                            bromide                                                                            228°-229°                                                               ethylenebromohydrin                             8    3,4-dichlorophenacyl                                                                      bromide                                                                            212°-214°                                                               3,4-dichlorophenacyl-                                                         bromide                                         9    phenethyl   bromide                                                                            209°-210°                                                               β-bromoethylbenzene                        10   3-chloropropen-2-yl                                                                       chloride                                                                           168°-169°                                                               1,3-dichloropropene                             11   benzyl      bromide                                                                            198°-199°                                                               benzyl bromide                                  12   4-chlorobenzyl                                                                            chloride                                                                           187°-188°                                                               4-chlorobenzyl                                                                chloride                                        13   2,4-dichlorobenzyl                                                                        chloride                                                                           172°-173°                                                               2,4-dichlorobenzyl                                                            chloride                                        14   3,4-dichlorobenzyl                                                                        chloride                                                                           158.5°-160°                                                             3,4-dichlorobenzyl                                                            chloride                                        __________________________________________________________________________

EXAMPLE 15

3,5-Dichloro-β-dimethylamino-p-phenetidine (15 grams) and 2-methylallylchloride (5.6 grams) are dissolved in 140 milliliters of acetonitrile.The reaction mixture is heated at a temperature of about 60°-65°C. for32 hours and then cooled. The reaction mixture is filtered, and the[2-(4-amino-2,6-dichlorophenoxy)ethyl]dimethyl(2-methylallyl)-ammoniumchloride product is collected as a filter cake, washed with acetonitrileand dried. The purified[2-(4-amino-2,6-dichlorophenoxy)ethyl]dimethyl(2-methylallyl)-ammoniumchloride product is found to melt at 189°-191°C.

EXAMPLE 16

3,5-Dibromo-β-diethylamino-p-phenetidine (14 grams; 0.038 mole) and 4.85grams of allyl bromide are dissolved in 140 milliliters of acetonitrile.The mixture is heated with stirring at a temperature of 60°-65°C. for 4hours, stirred at room temperature overnight, then heated at 60°-65°C.for about 18 hours and cooled. The crystalline product is separated byfiltration of the mixture and the[2-(4-amino-2,6-dibromophenoxy)ethyl]diethyl(allyl)ammonium bromideproduct is obtained as a crystalline solid melting at 205°-207°C.

EXAMPLE 17

3,5-Dibromo-4-(3-dimethylaminopropoxy)aniline (5 grams) and 1.8 grams ofallyl bromide are mixed with 30 milliliters of acetonitrile. Crystalformation and a slight temperature rise is observed. The reactionmixture is heated at a temperature of 50°-60°C. for 4 hours withstirring, then held overnight and filtered. The[3-(4-amino-2,6-dibromophenoxy)propyl]dimethyl(allyl)ammonium bromideproduct is collected as a filter cake, dried in air, and obtained as abuff colored crystalline solid melting at 167°-169°C.

EXAMPLE 18

3,5-Dibromo-β-dimethylamino-p-phenetidine (13.5 grams; 0.04 mole) isdissolved in 150 milliliters of ethyl acetate at room temperature.Cyanomethyl benzenesulfonate (8 grams; 0.04 mole) is added dropwise tothe solution with stirring. The reaction mixture is held overnight atroom temperature. The reaction mixture is filtered. The[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-nitriloethyl)-ammoniumbenzenesulfonate product is collected as a filter cake. The product istaken up in hot acetonitrile and the solution is filtered. The hotfiltrate is cooled, whereupon a crystalline solid precipitate forms, andfiltered. The purified[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-nitriloethyl]ammoniumbenzenesulfonate product is collected as a filter cake, air dried, andfound to melt at 173.5°-175°C. The structure of the product is confirmedby infrared and nuclear magnetic resonance spectroscopy. The product isfound by combustion analysis to have carbon, hydrogen and nitrogencontents of 40.6, 3.93 and 7.87 percent, respectively, as compared withthe theoretical contents of 40.39, 3.96 and 7.85 percent, respectively,calculated for the named structure.

EXAMPLE 19

3,5-Dibromo-β-dimethylamino-p-phenetidine (25.4 grams; 0.075 mole) isdissolved in 300 milliliters of acetonitrile at room temperature. Allylmethanesulfonate (10.2 grams; 0.075 mole) is rapidly added to thesolution with stirring. The reaction mixture is heated at a temperatureof 35°-45°C. for 5 hours with continued stirring. Formation of aprecipitate is observed in the mixture, beginning about 10 minutes afteraddition of the allyl methanesulfonate and continuing through theheating period. The reaction mixture is cooled and filtered. The[2-(4-amino-2,6-dibromophenoxy)-ethyl]dimethyl(allyl)ammoniummethanesulfonate product is collected as a filter cake, dried, andrecrystallized from n-propanol. The product is found to melt at202°-203°C. The structure of the product is confirmed by infrared andnuclear magnetic resonance spectroscopy. The product is found bycombustion analysis to have carbon, hydrogen and nitrogen contents of35.35, 4.65 and 6.13 percent, respectively, as compared with thetheoretical contents of 35.45, 4.68 and 5.91 percent, respectively,calculated for the named structure.

EXAMPLE 20

α,3,5-Tribromo-p-phenetidine (20.2 grams) is dissolved in 150milliliters of acetonitrile, then mixed with a solution of 6 grams ofquinuclidine in 100 milliliters of acetonitrile. The reaction mixture isheated at a temperature of about 50°C. for 4 hours and then cooled, andheld for 48 hours at ambient temperature. The reaction mixture isfiltered, and the [2-(4-amino-2,6-dibromophenoxy)-ethyl] quinuclidiniumbromide product is collected as a filter cake, washed with acetonitrileand dried. The purified [2-(4-amino-2,6-dibromophenoxy)ethyl]quinuclidinium bromide product is found to melt at 239°-241°C. Theproduct corresponds to the formula: ##SPC5##

EXAMPLE 21

3,5-Dibromo-β-pyrrolidino-p-phenetidine (15 grams) and allyl bromide(5.25 grams) are mixed in 50 milliliters of acetonitrile. The reactionmixture is heated at a temperature of about 60°-70°C. for 4 hours andthen cooled. The reaction mixture is diluted with ethylacetate, and the[2-(4-amino-2,6-dibromophenoxy)ethyl] allyl pyrrolidinium bromideproduct is collected by decantation. The product is taken up inisopropanol, mixed with excess hydrogen bromide in isopropanol and themixture is cooled and filtered. The1-[2-(4-amino-2,6dibromophenoxy)ethyl]-1-allyl pyrrolidinium bromidehydrobromide product is found to melt at 211°-213°C.

EXAMPLE 22

In a procedure similar to that described in Example 21,1-[2-(4-amino-2,6-dibromophenoxy)ethyl]-1-allyl piperidinium bromidehydrobromide, melting at 207°-209°C., is prepared by reacting 17 gramsof 3,5-dibromo-β-piperidino-p-phenetidine and 5.75 grams of allylbromide in 50 milliliters of acetonitrile.

EXAMPLE 23

3,5-Dibromo-β-hexamethyleneamino-p-phenetidine (16.8) grams) and allylbromide (5.47 grams) are dissolved in 70 milliliters of acetonitrile.The reaction mixture is heated at a temperature of about 60°C. for 2hours and then cooled. The reaction mixture is filtered, and the[2-(4-amino-2,6-dibromophenoxy)ethyl]-1-allylhexahydroazepinium bromideproduct, corresponding to the formula ##SPC6##

is collected as a filter cake, washed with acetonitrile and dried. Thepurified product is found to melt at 177°-179°C.

EXAMPLE 24

In a procedure similar to that described above in Example 20,β,3,5-tribromo-p-phenetidine and 3-picoline are reacted together toprepare 1-[2-(4-amino-2,6-dibromo-phenoxy)ethyl]-3-picolinium bromide,melting at 218°-220°C.

EXAMPLE 25

In a procedure similar to that of Example 17,3,5-dibromo-4'-(4-dimethylaminobutoxy) aniline is reacted with allylbromide to prepare [4-(4-amino-2,6-dibromophenoxy)-butyl]dimethyl(allyl)ammonium bromide as a pale yellow crystalline solid melting at184°-186°C.

In procedures similar to those described above in Examples 1-25, thefollowing quaternary ammonium salt compounds are prepared:

1-[3-(4-ethylamino-2,6-dibromophenoxy)propyl]-1-allyl-2-methylpyrrolidinium bromide hydrobromide;

[4-(4-dimethylamino-2,6-dichlorophenoxy)butyl]-dibutyl(3-butynyl)ammoniummethanesulfonate;

1-[2-(4-amino-2,6-diiodophenoxy)ethyl]-3,4-dimethyl pyridinium bromidehydrobromide;

[3-(4-hexylamino-2,6-dichlorophenoxy)propyl]dimethyl-(4-nitrilobutyl)ammoniumchloride;

[2-(4-amino-2,6-dibromophenoxy)ethyl]diethyl(3-butenyl)ammoniump-toluenesulfonate;

[2-(4-amino-2,6-diiodophenxoy)ethyl]dimethyl[4-(3,4-dichlorophenyl)butyl]ammoniumchloride;

1-[3-(4-ethylamino-2,6-dichlorophenoxy)propyl]-1-(2-propynyl)-hexahydroazepiniumchloride hydrochloride; and

[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(3-keto butyl)ammoniumbenzenesulfonate.

The following examples further illustrate the invention, particularly asto the use of the compounds in controlling cardiac arrhythmias.

EXAMPLE 26

Ventricular tachycardia is produced in dogs in a method similar to themethod of Lucchesi and Hardman (J. Pharmacol. Exptl. Therap., 132, 372,1961) by the administration of ouabain. In such operations, a dog isanesthetized by the intravenous administration of pentobarbital sodiumat a dosage rate of 30 milligrams per kilogram. A femoral artery iscannulated with polyethylene tubing for measurements of blood pressure.A femoral vein is similarly cannulated for administration of ouabain andadministration of the test compound. Hypodermic needle electrodes areemployed for recording electrocardiograms. In such operations, ouabainis administered intravenously by infusion at a constant rate via thecannulated femoral vein. The infusion rate is 35 micrograms of ouabainper kilogram of animal body weight per hour. Within 1 to 1.5 hoursfollowing the start of the infusion, a ventricular tachycardia is seento develop.

After ventricular tachycardia is observed, a test compound isadministered intravenously by administration of varying amounts of acomposition comprising 50 milligrams of the test compound as a sterilesolution in 10 milliliters of water containing 0.9 percent sodiumchloride. Each dose is administered slowly over a period of 15 to 30seconds. The compound is administered at an initial dosage rate of 0.25milligram of test compound per kilogram of animal body weight. Bloodpressure and electrocardiogram are observed for 5 minutes afteradministration. When a complete conversion from the arrhythmic conditionto normal sinus rhythm is not observed within the 5 minute period, asecond dose of 0.50 milligram of the test compound per kilogram isadministered by a similar procedure and blood pressure and heartbeat aresimilarly observed for 5 minutes. When complete conversion of theventricular tachycardia to normal sinus rhythm is not observed, thedosage is increased two-fold every five minutes until completeconversion is obtained. The animal is then observed and the duration ofthe period of normal cardiac rhythm produced by administration of thetest compound is recorded as the duration of antiarrhythmic activity.The termination of the period of normal activity is marked by thereappearance of ventricular tachycardia or fibrillation as indicated bythe electrocardiogram observations. The antiarrhythmic dosage of testcompound sufficient to bring about a complete conversion of thecuabain-induced tachycardia, and the duration of the period of normalcardiac activity are set out below.

    ______________________________________                                        Cmpd. of Conversion Dose      Duration                                        Ex. No.  (Milligrams per Kilogram)                                                                          in Minutes                                      ______________________________________                                        1        0.5                  15                                              2        1                    2.6                                                      2                    3.5                                             3        1                    12.5                                            4        0.5                  24                                              5        1                    11                                              6        1                    6                                               7        1                    25                                              8        16                   10                                              9        2                    3.5                                             10       1                    3                                               11       1                    8.5                                             12       1                    9.5                                             13       0.5                  4                                               14       2                    14                                              15       0.5                  4.5                                             16       2                    6.5                                             17       1                    6                                               18       1                    4                                               19       1                    17.5                                                     2                    39.0                                            20       0.5                  1                                               21       2                    1.5                                             22       1                    6.5                                             23       0.5                  3.3                                                      1                    7.5                                             24       0.5                  38                                              25       2                    26                                              ______________________________________                                    

EXAMPLE 27

The procedure of Example 26 is repeated, employing the compound ofExample 1, [2-(4-amino-2,6-dibromophenoxy)-ethyl]-dimethyl(2-methylallyl)ammoniumchloride, as a test compound. In these operations two groups of threedogs each are administered the test compound intravenously atanti-arrhythmic dosage rates of 1 and 2 milligrams per kilogram afterectopic ventricular rhythms have been established by continuous infusionof cuabain. Complete conversion of the arrhythmias to sinus rhythm isobserved in all the dogs, with mean durations of sinus rhythm of 12.7and 26.5 minutes, respectively, being observed in the groupsadministered 1 and 2 milligrams of the test compound, respectively, perkilogram.

EXAMPLE 28

[2-(4-Amino-2,6-dibromophenoxy)ethyl]dimethyl-(2-methylallyl)ammoniumchloride is employed to alleviate multifocal ventricular arrhythmiasinduced by administration of n-hexane and epinephrine. In theseoperations, dogs are anesthetized by intravenous administration of 30milligrams of pentobarbital sodium per kilogram. Transient ventriculararrhythmias are induced by a modification of the method of Garb andChenowith, J. Pharmacol. Exp. Ther. 94; 12 (1948) in which the heart issensitized by intratracheal injection of 0.04 milliliter of n-hexane perkilogram, followed in 15 seconds by rapid intravenous administration of1-epinephrine bitrate at a dosage rate of 10 micrograms per kilogram.Such procedure produces a transient arrhythmia lasting about 10 seconds.Duration of protection by a test compound is evaluated by repeating then-hexane and epinephrine challenge periodically and monitoringelectrocardiogram and arterial blood pressure. In such operations theabove-named quaternary ammonium compound is found to give excellentprotection against the arrhythmias when administered intravenously at adosage rate of one milligram per kilogram, the duration ofantiarrhythmic effect lasting about 1 hour. When the same compound isadministered at a dosage rate of 2 milligrams per kilogram, the durationof protection is found to be greater than 2 hours.

In similar operations, dosages of 5 to 10 milligrams per kilogram arefound to be required to obtain similar antiarrhythmic effects when theknown antiarrhythmic agent, quinidine sulfate, is employed as a testcompound.

In other operations carried out by procedures similar to that describedby Bacaner, American Journal of Cardiology, 21, 504 (1968); theintravenous administration of[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl) ammoniumchloride to electrically paced dogs is found to provide substantialincreases in the threshold for electrically induced ventricularfibrillation.

EXAMPLE 29

An experimental occlusion of the anterior descending coronary artery isproduced in dogs according to the method of Harris, Circulation 1, 1318(1950). Following surgery the animals are given apenicillin-streptomycin preparation and allowed to recover for 18-24hours. The animals are given 3 milligrams per kilogram of morphinesulfate as an analgetic and sedative to allow handling.Electrocardiograms are recorded both before and after administration of[2-(2-amino-2,6-dibromophenoxy)ethyl]dimethyl-(2-methylallyl)ammoniumchloride to the test animals. The incidence of abnormal complexes(premature ventricular contractions and atrioventricular nodal beats)per minute is recorded as a percentage of total beats per minute. In onesuch operation the test compound is administered by intravenous infusionat rates of 1, 2, 2 and 2 milligrams per kilogram at intervals of 10 to15 minutes. A marked decrease in heart beat rate is observed with aconcomitant decrease in percentage of abnormal beats per minutefollowing the first infusion. Following the last infusion of testcompound the heartbeat rate is observed to have decreased from a rate ofover 160 beats per minute prior to the first infusion to about 90-100beats per minute. The incidence of ectopic beats at this time hasdecreased from a pre-treatment level of 100 percent abnormal beats perminute to below 60 percent, reaching zero (100 percent normal beats)within about 10 minutes after the last infusion. The lower heartbeatrate and low incidence of abnormal beats (generally 0 to 20 percent ofthe total beats per minute are abnormal) is found to persist for 2 hoursfollowing the last infusion of test compound, at which time theexperiment is terminated.

In similar operations, the same test compound is infused at dosages of1, 2 and 4 milligrams per kilogram at intervals over a forty minuteperiod. Prior to infusion the incidence of abnormal beats is 100percent. Within about eight minutes following the last infusion, asubstantially complete conversion to sinus rhythm is obtained. Theincidence of abnormal beats is found to remain at zero with occasionalbrief periods of slight arrhythmia (2-5 percent abnormal beats) for 2.5hours following the last dosage of the test compound, when recording isterminated. Resumption of recording 215 minutes later indicates thatsignificant anti-arrhythmic effects are still exhibited.

In a similar operation the[2-(2-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammoniumchloride is administered orally in gelatin capsules. The test compoundis administered in multiple dosages of 30, 30 and 50 milligrams perkilogram over a period of 150 minutes. Periods of reduced frequency ofabnormal heart beats are noted beginning 10 minutes after administrationof the first dosage of test compound, the second and third dosesproviding further and more consistent antiarrhythmic effects. Beginningabout 25 minutes after the last dose of the test compound isadministered the electrocardiogram shows periods in which less than 10percent of the beats are abnormal interspersed with occasional periodsof arrhythmia. Antiarrhythmic effects continue to be observed until therecording is terminated 140 minutes after the last dose of testcompound.

EXAMPLE 30

[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl-(allyl)ammonium bromide isadministered to mice intravenously and orally. The animals arethereafter sacrificed and blood and heart tissue analyses are carriedout to ascertain the concentration of test compound present. In suchoperations mice intravenously administered the test compound at a rateof 6 milligrams per kilogram are found to have blood levels of 27micrograms of test compound per milliliter 10 seconds after injection,2.1 micrograms per milliliter 3 minutes after injection. Analysis ofheart tissue indicates a concentration of 5.5 micrograms of testcompound per gram of tissue 10 minutes after injection. Similar analysesare carried out with animals administered 6 milligrams of test compoundper kilogram orally. Thirty minutes after oral administration, blood andheart levels of 1.1 and 5.1 micrograms, respectively, of test compoundper milliliter of blood or gram of heart tissue, respectively, arefound.

Similar operations carried out by administration of[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)-ammoniumchloride to rabbits similarly indicate oral absorption of the testcompound. Significant blood and heart levels of test compound aredetected with both oral and intravenous administration.

EXAMPLE 31

An aqueous solution of [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammonium chloride is administered orally to severalgroups of male and female Sprague-Dawley derived rats and male andfemale Swiss mice (Cox strain). The compound is administered as singleoral dosages in varying amounts, and the animals are held to assesstoxicity twenty-four hours after administration of the compound. In suchoperations, the quaternary ammonium compound is found to have an LD₅₀ of758 milligrams per kilogram (mg/kg) in the male rats; 725 mg/kg in thefemale rats, 560 mg/kg in the male mice, and 550 mg/kg in the femalemice.

EXAMPLE 32

35 Grams of [2-(4-amino-2,6-dibromophenoxy)ethyl]-dimethyl(2-methylallyl)ammonium bromide is dissolved in 2 liters of sterilenormal physiological saline solution. The solution is filtered andfilled into 10 cubic centimeter (cc) syringes calibrated to permitinjection of the parenteral preparation in 0.5 cc increments. Thesyringes are individually packaged in containers adapted to maintainsterility and sterilized. The parenteral dosage units are each adaptedfor parenteral administration of the active compound in increments ofabout 8.75 milligrams each to a total of 175 milligrams.

Similar parenteral preparations are prepared using 25 grams of[2-(4-amino-2,6-dibromophenoxy)ethyl](ethyl)methyl-(allyl) ammoniummethane sulfonate in 1.5 liters of Lactated Ringer's Injection; 40 gramsof 1-[2-(4-amino-2,6-diiodophenoxy)ethyl)(2-methylallyl)3,4-dimethylpyrrolidinium bromide hydrobromide in steriledistilled water containing 0.4 percent chlorobutanol preservative; and10 grams of[3-(4-diethylamino-2,6-dichlorophenoxy)propyl]dimethyl(2-propynyl)-ammoniumchloride in 1 liter of Dextrose Injection.

EXAMPLE 33

100 Parts of[3-(4-amino-2,6-dichlorophenoxy)-propyl]dibutyl(3-butynyl)ammoniummethanesulfonate and 35 parts of lactose are mixed well with 751 partsof starch. The mixture is filled into gelatin capsules in the amount of0.4 grams per capsules are suitable for oral administration.

EXAMPLE 34

Tablets are prepared from a granulation comprising 50 parts by weight of[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammoniumchloride, 100 parts lactose, 3.5 parts magnesium stearate, 170 partsstarch, 50 parts microcrystalline cellulose, one part of apolyoxyethylene sorbitan monooleate surface active dispersing agent and0.4 part of F.D.&C. approved color. The granulation is screened andcompressed into tablets weighing about 0.287 gram each to prepare acomposition in dosage unit form adapted for oral administration toanimals. The dosage units are adapted to be employed in maintenanceantiarrhythmic therapy to inhibit recurrence of arrhythmias in animalssubject thereto, and prophylactically to animals in preparation forexposure to physical or chemical conditions creating a risk of cardiacarrhythmia. The tablets are administered to animals at the rate of oneor two tablets (containing 50 milligrams of active antiarrhythmic agent)per day.

What is claimed is:
 1. A composition useful as an antiarrhythmiccomprising a pharmaceutical carrier and from about 0.01 to about 98percent by weight of a quaternary ammonium compound corresponding to theformula: ##SPC7##wherein Y represents amino, or dilower-alkylamino; R₁and R₂ represent lower alkyl; R₃ independently represents lower alkenylor lower alkynyl X₁ and X₂ both represent halogen; A⁻ represents astoichiometric equivalent quantity of a pharmaceutically-acceptableanion; n represents one of the integers 2, 3 or 4; HX represents astoichiometric equivalent quantity of a pharmaceutically-acceptableacid; and m represents one of the integers 0 and
 1. 2. The compositionof claim 1 wherein Y is amino; n is 2, X₁ and X₂ are both chlorine orboth bromine; R₁ and R₂ together contain from 2 to 6 carbon atoms,inclusive; R₃ contains from 3 to 7 carbon atoms, inclusive; and whereinR₁, R₂ and R₃ together contain from 5 to 9 carbon atoms, inclusive. 3.The composition of claim 2 wherein the composition is a liquidparenterally-acceptable vehicle, and wherein the composition is asterile solution of the quaternary ammonium compound in the vehicle. 4.The composition of claim 2 wherein the composition is in a dosage unitform adapted for oral administration to animals, each of said unitscontaining from about 1 to about 500 milligrams of the quaternaryammonium salt compound.
 5. The composition of claim 2 wherein X₁ and X₂are both bromine, and R is allyl, 2-propynyl or 2-methylallyl.
 6. Thecomposition of claim 1 wherein m is
 0. 7. The composition of claim 1wherein the compound is a [2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammonium halide.
 8. The composition of claim 1 whereinthe compound is [4-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammonium chloride.
 9. A method for combatting cardiacarrhythmias which comprises administering to an animal a cardiacanti-arrhythmic amount of a quaternary ammonium compound correspondingto the formula: ##SPC8##wherein Y represents amino ordilower-alkylamino; R₁ and R₂ represent lower alkyl; R₃ independentlyrepresents lower alkenyl or lower alkynyl; X₁ and X₂ both representhalogen; A⁻ represents a stoichiometric equivalent quantity of apharmaceutically-acceptable anion; n represents one of the integers 2, 3or 4; HX represents a stoichiometric equivalent quantity of apharmaceutically-acceptable acid; and m represents one of the integers 0and
 1. 10. The method of claim 9 wherein the quaternary ammoniumcompound is administered by intravenous injection to a mammal sufferingcardiac arrhythmia.
 11. The method of claim 9 wherein the quaternaryammonium compound is administered orally to a cardiac arrhythmic mammal.12. The method of claim 9 wherein Y is amino; X₁ and X₂ are bothchlorine or both bromine, R₁ and R₂ together contain from 2 to 6 carbonatoms, inclusive; R₃ contains from 3 to 7 carbon atoms, inclusive; andwherein R₁, R₂ and R₃ together contain from 5 to 9 carbon atoms,inclusive.
 13. The method of claim 12 wherein n is 2, X₁ and X₂ are bothbromine or both chlorine, R₁ and R₂ are methyl or ethyl and R₃ is loweralkenyl or lower alkynyl of 3 or 4 carbon atoms.
 14. The method of claim13 wherein m is 0, R₁ and R₂ are methyl and R₃ is 2-methylallyl.
 15. Themethod of claim 14 wherein the compound is[2-(4-amino-2,6-dibromophenoxy)ethyl]dimethyl(2-methylallyl)ammoniumchloride.
 16. The method of claim 14 wherein the compound isadministered to a cardiac arrhythmic mammal.